Rate-controlled particles

ABSTRACT

Rate-controlled particles, comprising compounds of the formula 
     
       
         
         
             
             
         
       
     
     as a solid dispersion.

The present invention concerns pharmaceutical compositions in the formof rate-controlled particles, comprising compounds of the formula (I) to(VI)

(I) is an antiviral compound of formula

-   a N-oxide, a pharmaceutically acceptable addition salt or a    stereochemically isomeric form thereof, wherein-   Y is CR⁵ or N;-   A is CH, CR⁴ or N;-   n is 0, 1, 2, 3 or 4;-   Q is —NR¹R² or when Y is CR⁵ then Q may also be hydrogen;-   R¹ and R² are each independently selected from hydrogen, hydroxy,    C₁₋₁₂alkylcarbonyl, C₁₋₁₂alkyloxycarbonyl, aryl, amino, mono- or    di(C₁₋₁₂alkyl)-amino, mono- or di(C₁₋₁₂alkyl)aminocarbonyl wherein    each of the aforementioned C₁₋₁₂alkyl groups may optionally and each    individually be substituted with one or two substituents each    independently selected from hydroxy, C₂₋₆alkyloxy,    hydroxy-C₁₋₆alkyloxy, carboxyl, C₁₋₆alkyloxycarbonyl, cyano, amino,    imino, aminocarbonyl, aminocarbonylamino, mono- or    di(C₁₋₆alkyl)amino, aryl and Het; or-   R¹ and R² taken together may form pyrrolidinyl, piperidinyl,    morpholinyl, azido or mono- or di(C₁₋₁₂alkyl)aminoC₁₋₄-alkylidene;-   R³ is hydrogen, aryl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxy-carbonyl,    C₁₋₆alkyl substituted with C₁₋₆alkyloxycarbonyl; and-   each R⁴ independently is hydroxy, halo, C₁₋₆alkyl, C₁₋₆alkyloxy,    cyano, aminocarbonyl, nitro, amino, trihalomethyl,    trihalo-methyloxy, or when Y is CR⁵ then R⁴ may also represent    C₁₋₆alkyl substituted with cyano or aminocarbonyl;-   R⁵ is hydrogen or C₁₋₄alkyl;-   L is —X¹—R⁶ or —X²-Alk-R⁷ wherein    -   R⁶ and R⁷ each independently are phenyl or phenyl substituted        with one, two, three, four or five substituents each        independently selected from halo, hydroxy, C₂₋₆alkyl,        C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, formyl,        cyano, nitro, amino, and trifluoromethyl; or when Y is CR⁵ then        R⁶ and R⁷ may also be selected from phenyl substituted with one,        two, three, four or five substituents each independently        selected from aminocarbonyl, trihalomethyloxy and trihalomethyl;        or when Y is N then R⁶ and R⁷ may also be selected from indanyl        or indolyl, each of said indanyl or indolyl may be substituted        with one, two, three, four or five substituents each        independently selected from halo, hydroxy, C₁₋₆alkyl,        C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, formyl,        cyano, nitro, amino, and trifluoromethyl;    -   X¹ and X² are each independently —NR³—, —NH—NH—, —N═N—, —O—,        —S—, —S(═O)— or —S(═O)₂—;    -   Alk is C₁₋₄alkanediyl; or-   when Y is CR⁵ then L may also be selected from C₁₋₁₀alkyl,    C₃₋₁₀alkenyl, C₃₋₁₀alkynyl, C₃₋₇cycloalkyl, or C₁₋₁₀alkyl    substituted with one or two substituents independently selected from    C₃₋₇cycloalkyl, indanyl, indolyl and phenyl, wherein said phenyl,    indanyl and indolyl may be substituted with one, two, three, four or    where possible five substituents each independently selected from    halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl,    C₁₋₆alkyloxy-carbonyl, formyl, nitro, amino, trihalomethyl,    trihalomethyl-oxy and C₁₋₆alkylcarbonyl;-   aryl is phenyl or phenyl substituted with one, two, three, four or    five substituents each independently selected from halo, C₁₋₆alkyl,    C₁₋₆alkyloxy, cyano, nitro and trifluoromethyl;-   Het is an aliphatic or aromatic heterocyclic radical; said aliphatic    heterocyclic radical is selected from pyrrolidinyl, piperidinyl,    homopiperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and    tetrahydrothienyl wherein each of said aliphatic heterocyclic    radical may optionally be substituted with an oxo group; and said    aromatic heterocyclic radical is selected from pyrrolyl, furanyl,    thienyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl wherein    each of said aromatic heterocyclic radical may optionally be    substituted with hydroxy.

The compounds of formula (I) can be prepared according to the methodsdescribed in the patent applications with application numberPCT/EP99/02043 and PCT/EP99/02044.

(II) is an antiviral compound of formula

the N-oxides, the pharmaceutically acceptable addition salts, quaternaryamines and the stereochemically isomeric forms thereof, wherein-b¹=b²-C(R^(2a))=b³-b⁴=represents a bivalent radical of formula

—CH═CH—C(R^(2a))═CH—CH═  (b-1);

—N═CH—C(R^(2a))═CH—CH═  (b-2);

—CH═N—C(R^(2a))═CH—CH═  (b-3);

—N═CH—C(R^(2a))═N—CH═  (b-4);

—N═CH—C(R^(2a))═CH—N═  (b-5);

—CH═N—C(R^(2a))═N—CH═  (b-6);

—N═N—C(R^(2a))═CH—CH═  (b-7);

-   q is 0, 1, 2; or where possible q is 3 or 4;-   R¹ is hydrogen, aryl, formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyl,    C₁₋₆alkyloxycarbonyl, C₁₋₆alkyl substituted with formyl,    C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl;-   R^(2a) is cyano, aminocarbonyl, mono- or di(methyl)aminocarbonyl,    C₁₋₆alkyl substituted with cyano, aminocarbonyl or mono- or    di(methyl)aminocarbonyl, C₂₋₆alkenyl substituted with cyano, or    C₂₋₆alkynyl substituted with cyano;-   each R² independently is hydroxy, halo, C₁₋₆alkyl optionally    substituted with cyano or —C(═O)R⁶, C₃₋₇cycloalkyl, C₂₋₆alkenyl    optionally substituted with one or more halogen atoms or cyano,    C₂₋₆alkynyl optionally substituted with one or more halogen atoms or    cyano, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro,    amino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,    polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁶,    —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂, _NHC(═O)R⁶,    —C(═NH)R⁶ or a radical of formula

wherein each A independently is N, CH or CR⁶;

-   -   B is NH, O, S or NR⁶;    -   p is 1 or 2; and    -   R⁶ is methyl, amino, mono- or dimethylamino or polyhalomethyl;

-   L is C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₇cycloalkyl,    whereby each of said aliphatic group may be substituted with one or    two substituents independently selected from    -   C₃₋₇cycloalkyl,    -   indolyl or isoindolyl, each optionally substituted with one,        two, three or four substituents each independently selected from        halo, C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy, cyano, aminocarbonyl,        nitro, amino, polyhalomethyl, poly-halomethyloxy and        C₁₋₆alkylcarbonyl,    -   phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl,        wherein each of said aromatic rings may optionally be        substituted with one, two, three, four or five substituents each        independently selected from the substituents defined in R²; or

-   L is —X—R³ wherein    -   R³ is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl,        wherein each of said aromatic rings may optionally be        substituted with one, two, three, four or five substituents each        independently selected from the substituents defined in R²; and    -   X is —NR¹—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, —S(═O)—        or —S(═O)₂—;

-   Q represents hydrogen, C₁₋₆alkyl, halo, polyhaloC₁₋₆alkyl or —NR⁴R⁵;    and

-   R⁴ and R⁵ are each independently selected from hydrogen, hydroxy,    C₁₋₁₂alkyl, C₁₋₁₂alkyloxy, C₁₋₁₂alkylcarbonyl,    C₁₋₁₂alkyloxy-carbonyl, aryl, amino, mono- or di(C₁₋₁₂alkyl)amino,    mono- or di(C₁₋₁₂alkyl)aminocarbonyl wherein each of the    aforementioned C₁₋₁₂alkyl groups may optionally and each    individually be substituted with one or two substituents each    independently selected from hydroxy, C₁₋₆ alkyloxy,    hydroxyC₁₋₆alkyloxy, carboxyl, C₁₋₆alkyloxycarbonyl, cyano, amino,    imino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,    polyhalomethyloxy, poly-halomethylthio, —S(═O)_(p)R⁶,    —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁶,    —C(═NH)R⁶, aryl and Het; or

-   R⁴ and R⁵ taken together may form pyrrolidinyl, piperidinyl,    morpholinyl, azido or mono- or di(C₁₋₁₂alkyl)aminoC₁₋₄alkylidene;

-   Y represents hydroxy, halo, C₃₋₇cycloalkyl, C₂₋₆alkenyl optionally    substituted with one or more halogen atoms, C₂₋₆alkynyl optionally    substituted with one or more halogen atoms, C₁₋₆alkyl substituted    with cyano or —C(═O)R⁶, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,    carboxyl, cyano, nitro, amino, mono- or di(C₁₋₆alkyl)amino,    polyhalomethyl, polyhalomethyloxy, poly-halomethylthio,    —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂,    —NHC(═O)R⁶, —C(═NH)R⁶ or aryl;

-   aryl is phenyl or phenyl substituted with one, two, three, four or    five substituents each independently selected from halo, C₁₋₆alkyl,    C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro, poly-haloC₁₋₆alkyl and    polyhaloC₁₋₆alkyloxy;

-   Het is an aliphatic or aromatic heterocyclic radical; said aliphatic    heterocyclic radical is selected from pyrrolidinyl, piperidinyl,    homopiperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and    tetrahydrothienyl wherein each of said aliphatic heterocyclic    radical may optionally be substituted with an oxo group; and said    aromatic heterocyclic radical is selected from pyrrolyl, furanyl,    thienyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl wherein    each of said aromatic heterocyclic radical may optionally be    substituted with hydroxy.

The compounds of formula (II) can be prepared according to the methodsdescribed in the U.S. patent applications with application No.60/143,962 and 60/107,792.

(III) is an antiviral compound of formula

a N-oxide, a pharmaceutically acceptable addition salt, a quaternaryamine or a stereochemically isomeric form thereof, wherein-a¹=a²-a³=a⁴- represents a bivalent radical of formula

—CH═CH—CH═CH—  (a-1);

—N═CH—CH═CH—  (a-2);

—N═CH—N═CH—  (a-3);

—N═CH—CH═N—  (a-4);

—N═N—CH═CH—  (a-5);

-   n is 0, 1, 2, 3 or 4; and in case -a¹=a²-a³=a⁴- is (a-1), then n may    also be 5;-   R¹ is hydrogen, aryl, formyl, C₁₋₆alkylcarbonyl,    C₁₋₆alkyloxycarbonyl, C₁₋₆alkyl substituted with formyl,    C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl; and-   each R² independently is hydroxy, halo, C₁₋₆alkyl optionally    substituted with cyano or —C(═O)R⁴, C₃₋₇cycloalkyl, C₂₋₆alkenyl    optionally substituted with one or more halogen atoms or cyano,    C₂₋₆alkynyl optionally substituted with one or more halogen atoms or    cyano, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro,    amino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,    polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁴,    —NH—S(═O)_(p)R⁴, —C(═O)R⁴, —NHC(═O)H, —C(═O)NHNH₂, _NHC(═O)R⁴,    —C(═NH)R⁴ or a radical of formula

wherein each A independently is N, CH or CR⁴;

-   -   B is NH, O, S or NR⁴;    -   p is 1 or 2; and    -   R⁴ is methyl, amino, mono- or dimethylamino or polyhalomethyl;

-   L is C₄₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₇cycloalkyl, whereby    each of said aliphatic group may be substituted with one or two    substituents independently selected from    -   C₃₋₇cycloalkyl,    -   indolyl or isoindolyl, each optionally substituted with one,        two, three or four substituents each independently selected from        halo, C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy, cyano, aminocarbonyl,        nitro, amino, polyhalomethyl, poly-halomethyloxy and        C₁₋₆alkylcarbonyl,    -   phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl,        wherein each of said aromatic rings may optionally be        substituted with one, two, three, four or five substituents each        independently selected from the substituents defined in R²; or

-   L is —X—R³ wherein    -   R³ is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl,        wherein each of said aromatic rings may optionally be        substituted with two, three, four or five substituents each        independently selected from the substituents defined in R²; and    -   X is —NR¹—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, —S(═O)—        or —S(═O)₂—;        aryl is phenyl or phenyl substituted with one, two, three, four        or five substituents each independently selected from halo,        C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro,        poly-haloC₁₋₆alkyl and polyhaloC₁₋₆alkyloxy.

The compounds of formula (III) can be prepared according to the methodsdescribed in the U.S. patent application with application No.60/107,799.

(IV) is an antiviral compound of formula

the pharmaceutically acceptable acid addition salts and thestereochemically isomeric forms thereof, wherein

-   R¹ and R² are each independently selected from hydrogen; hydroxy;    amino; C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylcarbonyl;    C₁₋₆alkyl-oxycarbonyl; Ar¹; mono- or di(C₁₋₆alkyl)amino; mono- or    di(C₁₋₆alkyl)aminocarbonyl; dihydro-2(3H)-furanone; C₁₋₆alkyl    substituted with one or two substituents each independently selected    from amino, imino, aminocarbonyl, aminocarbonyl-amino, hydroxy,    hydroxyC₁₋₆alkyloxy, carboxyl, mono- or di(C₁₋₆alkyl)amino,    C₁₋₆alkyloxycarbonyl and thienyl; or-   R¹ and R² taken together may form pyrrolidinyl, piperidinyl,    morpholinyl, azido or mono- or di(C₁₋₆alkyl)aminoC₁₋₄-alkylidene;-   R³ is hydrogen, Ar¹, C₁₋₆alkylcarbonyl, C₁₋₆ alkyl,    C₁₋₆alkyloxy-carbonyl, C₁₋₆alkyl substituted with    C₁₋₆alkyloxycarbonyl; and-   R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently selected from hydrogen,    hydroxy, halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, amino-carbonyl,    nitro, amino, trihalomethyl or trihalomethyloxy-   L is C₁₋₁₀alkyl; C₃₋₁₀alkenyl; C₃₋₁₀alkynyl; C₃₋₇cycloalkyl; or-   L is C₁₋₁₀alkyl substituted with one or two substituents    independently selected from C₃₋₇cycloalkyl; indolyl or indolyl    substituted with one, two, three or four substituents each    independently selected from halo, C₁₋₆alkyl, cyano, aminocarbonyl,    nitro, amino, trihalomethyl, trihalo-methyloxy, C₁₋₆alkylcarbonyl;    phenyl or phenyl substituted with one, two, three, four or five    substituents each independently selected from halo, hydroxy,    C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl,    trihalo-methyloxy, C₁₋₆alkylcarbonyl; and,    Ar¹ is phenyl, or phenyl substituted with one, two or three    substituents each independently selected from halo, C₁₋₆alkyl,    cyano, nitro or trifluoromethyl; with the proviso that compounds (a)    to (o)

Co. No. Alk R¹/R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ a 1-(4-(2-methylpropyl)phenyl)ethylH/H H CH₃ H H H H b 1-(4-(2-methylpropyl)phenyl)ethyl H/H H H H NO₂ H Hc 1-(4-(2-methylpropyl)phenyl)ethyl H/H C₆H₅ H H H H H d1-(4-(2-methylpropyl)phenyl)ethyl H/H H NO₂ H CH₃ H H e1-(4-(2-methylpropyl)phenyl)ethyl H/H H H H NH₂ H H f4-(2-methylpropyl)phenylmethyl H/H H H CF₃ H H H g1-(4-(2-methylpropyl)phenyl)ethyl H/H H H H Cl H H h4-(2-methylpropyl)phenylmethyl H/H H H H H H H i3,4-dimethoxyphenylmethyl H/H H H H H H H j 2,3-dimethoxyphenylmethylH/H H H H H H H k 3,4-diethoxyphenylmethyl H/H H H H H H H 12-(3,5-(1,1-dimethylethyl)-4- H/H H H H H H H hydroxy-phenyl)ethyl m2-(3,5-(1,1-dimethylethyl)-4- H/H H H t-Bu OH t-Bu Hhydroxy-phenyl)ethyl n Phenylmethyl H/H H CH₃ H H H H o Phenylmethyl H/HH H H H H Hare not included.

The compounds of formula (IV) can be prepared according to the methodsdescribed in EP-A-0834507.

(V) is an antifungal compound of formula

the N-oxide forms, the pharmaceutically acceptable acid addition saltsand stereochemically isomeric forms thereof, wherein

-   n is zero, 1, 2 or 3;-   X is N or CH;-   each R¹ independently is halo, nitro, cyano, amino, hydroxy,    C₁₋₄alkyl, C₁₋₄alkyloxy or trifluoromethyl;-   R² is hydrogen; C₃₋₇alkenyl; C₃₋₇alkynyl, aryl; C₃₋₇cycloalkyl;    C₁₋₆alkyl or C₁₋₆alkyl substituted with hydroxy, C₁₋₄alkyloxy,    C₃₋₇cycloalkyl or aryl;-   R³ and R⁴ each independently are hydrogen, C₁₋₆alkyl,    C₃₋₇cyclo-alkyl or aryl; or-   R³ and R⁴ taken together form a bivalent radical —R³—R⁴— of formula:

-   -   wherein R^(5a), R^(5b), R^(5c), R^(5d) each independently are        hydrogen, C₁₋₆alkyl or aryl; and        aryl is phenyl or phenyl substituted with one, two or three        substituents selected from halo, nitro, cyano, amino, hydroxy,        C₁₋₄alkyl, C₁₋₄alkyloxy or trifluoromethyl.

The compounds of formula (V) can be prepared according to the methodsdescribed in WO 99/02523.

(VI) is an apolipoprotein-B synthesis inhibitor of formula

the N-oxides, the stereochemically isomeric forms thereof, and thepharmaceutically acceptable acid addition salts, wherein A and B takentogether form a bivalent radical of formula:

—N═CH—  (a),

—CH═N—  (b),

—CH₂—CH₂—  (c),

—CH═CH—  (d),

—C(═O)—CH₂—  (e),

—CH₂—C(═O)—  (f),

in the bivalent radicals of formula (a) and (b) the hydrogen atom may bereplaced by C₁₋₆alkyl; in the bivalent radicals of formula (c), (d),(e), (f), one or two hydrogen atoms may be replaced by C₁₋₆alkyl;

-   R¹ is hydrogen, C₁₋₆alkyl or halo;-   R² is hydrogen or halo;-   R³ is hydrogen; C₁₋₈alkyl; C₃₋₆cycloalkyl; or C₁₋₈alkyl substituted    with hydroxy, oxo, C₃₋₆cycloalkyl or aryl;-   Het is a heterocycle selected from the group consisting of pyridine;    pyridine substituted with one or two substituents selected from    C₁₋₆alkyl, hydroxy, trihalomethyl, amino, mono- or    di(C₁₋₆alkyl)amino or aryl; pyrimidine; pyrimidine substituted with    one or two substituents selected from C₁₋₆alkyl, hydroxy,    trihalomethyl, amino, mono- or di(C₁₋₆alkyl)-amino or aryl;    tetrazole; tetrazole substituted with C₁₋₆alkyl or aryl; triazole;    triazole substituted with one or two substituents selected from    C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy, trihalomethyl, amino, mono- or    di(C₁₋₆alkyl)-amino; thiadiazole; thiadiazole substituted with one    or two substituents selected from C₁₋₆alkyl, hydroxy, trihalomethyl,    amino, mono- or di(C₁₋₆alkyl)-amino; oxadiazole substituted with one    or two substituents selected from C₁₋₆alkyl, hydroxy, trihalomethyl,    amino, mono- or di(C₁₋₆alkyl)amino; imidazole; imidazole substituted    with one or two substituents selected from C₁₋₆alkyl, hydroxy,    trihalomethyl, amino, mono- or di(C₁₋₆alkyl)amino; thiazole;    thiazole substituted with one or two substituents selected from    C₁₋₆alkyl, hydroxy, trihalomethyl, amino, mono- or    di(C₁₋₆alkyl)amino; oxazole; oxazole substituted with one or two    substituents selected from C₁₋₆alkyl, hydroxy, trihalomethyl, amino,    mono- or di(C₁₋₆alkyl)amino;-   aryl is phenyl or phenyl substituted with C₁₋₆alkyl or halo.

The heterocyclic radical “Het” is bound to the sulfur atom via a carbonatom.

The compounds of formula (VI) can be prepared according to the methodsdescribed in WO 96/13499.

The particles comprise the compounds of formula (I) to (VI) as a soliddispersion in a polymeric matrix, wherein the poly-meric matrix isconsisting of a homo- or copolymer of N-vinyl-pyrrolidone. Furthermore,the invention concerns a process for manufacturing of such particles andpharmaceutical dosage forms comprising such particles.

The compounds of formula (I) to (VI) contained in the particles showpoor bio-availability.

In order to improve the dissolution characteristics the compounds aredispersed in a polymeric matrix, preferably by using a melt-extrusionprocess.

EP-A 0 240 904 discloses a method for producing solid pharmaceuticalforms by extrusion of polymer melts which contain active substances,using as polymers homo- or copolymers of N-vinyl-pyrrolidone.

EP-B 0 580 860 discloses a method for producing solid dispersions ofdrug substances in a polymeric matrix using a twin screw extruder.

It is an object of the present invention to provide rate-controlledpharmaceutical forms containing the aforementioned compounds.

We have found that this object is achieved by the particles defined atthe outset.

Preferred compounds according to the invention are:

-   4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzo-nitrile;-   4-[[2-[(cyanophenyl)amino]-4-pyrimidinyl]amino]-3,5-dimethyl-benzonitrile;-   4-[[4-amino-5-chloro-6-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]-amino]benzonitrile;-   4-[[5-chloro-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]-amino]benzonitrile;-   4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-2-pyrimidinyl]-amino]benzonitrile;-   4-[[4-amino-5-chloro-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;-   4-[[5-bromo-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]-amino]benzonitrile;-   4-[[4-amino-5-chloro-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile;-   4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile;-   4-[[4-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]-benzonitrile;-   4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]-amino]benzonitrile;-   4-[[4-[(2,6-dichlorophenyl)methyl]-6-(hydroxyamino)-1,3,5-triazin-2-yl]amino]benzonitrile;-   1-[4-[4-[4-[[4-(2,4-difluorophenyl)-4-(1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxolan-2-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-3-(1-methylethyl)-2-imidazolidinone;-   (−)-[2S-[2alpha,4alpha(S*)]]-4-[4-[4-[4-[[2-(4-chlorophenyl)-2-[[(4-methyl-4H-1,2,4-triazol-3-yl)thio]methyl]-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methyl-propyl)-3H-1,2,4-triazol-3-one,    a N-oxide, a pharmaceutically acceptable addition salt or a    stereochemically isomeric form thereof.

According to the present invention the term “rate-controlled” means thatdepending on the composition of the matrix the particles can showinstant release of the active ingredient or modified release (sustainedrelease).

The compounds according to the invention are homogeneously dispersed ina polymer matrix consisting of a homopolymer of N-vinylpyrrolidone or,preferably, a copolymer of N-vinyl-pyrrolidone. A preferred copolymer isa copolymer of N-vinyl-pyrrolidone and vinyl acetate, especially acopolymer obtained from 60% b.w. of NVP and 40% b.w. of vinylacetate.

The polymers show Fikentscher K values of from 17 to 90, preferably a Kvalue of 30 (for the definition of the K value see “H. Fikentscher,Cellulose-Chemie” (1932), 58-64 and 71-74).

The polymeric matrix component is used in amounts of from 40 to 70,preferably of from 50 to 65% b.w. of the total weight of the particles.

In a preferred embodiment of the invention the polymeric matrix furthercomprises a surfactant, preferably a surfactant with a HLB-value of10-18 (HLB: Hydrophilic Lipophilic Balance). Especially preferredsurfactants are selected form the group consisting of low molecularweight polyoxyethylene polyoxy-propylene block copolymers with a meanmolecular weight of 1000 to 6000 g/mol, and hydrogenated castor oilwhich can be modified with polyethylene glycol.

The amounts of surfactants used lies in the range of up to 20% b.w.,preferably 5 to 15% b.w., of the particles.

In another preferred embodiment the matrix further comprises an organiccarboxylic acid in amounts of up to 5% b.w. of the particles.

In another preferred embodiment of the invention the polymeric matrixfurther comprises hydroxypropyl methyl cellulose in amounts of up to 25%b.w., preferably from 5 to 10% b.w.

The particles of the present invention are prepared as solid dispersionsof the active compounds in a polymeric matrix. The term “soliddispersion” is well known in the art and means a dispersion consistingof solid components. Preferably solid dispersions are in the form ofsolid solutions wherein the active ingredients are molecularly dispersedin the polymeric matrix.

Such solid dispersion is preferably obtained by forming a homogeneousmixture of the components in the form of a melt, extruding said melt andshaping of the extrudate. The melting is effected by the input ofthermal and/or mechanic energy. Depending on the composition of thematrix, the melting takes place in the range of from 40° C. to 190° C.,preferably 50 to 150° C.

The suitable temperature range depends on the glass transitiontemperature of the polymer component, the properties of the activeingredients and further additives. The optimal temperature range can beestablished by a few simple tests.

The mixing of the active substances with the polymer and additionalcomponents of the matrix can take place before or after the melting ofthe polymer. Preferably the process is solvent-free which means that noadditional organic solvents or water are added.

The plastification and melting preferably can take place in an extruder,a kneader or a mixing reactor, preferably in an extruder having one ormore screws which may rotate in the same direction or oppositedirections, especially in a twin screw extruder. The latter can beoperated with or without kneading elements, but use of kneading elementsis preferred because mixing is better.

The still plastic material is extruded through a die or a breaker plateand then shaped into particles. This may be effected by milling andsubsequent sieving the cooled extrudate. The preferred particle size forinstant release forms lies in the range of from 0.5 to 1.5 mm.

The particles, optionally together with conventional pharmaceuticallyacceptable excipients, may be further processed to conventionalpharmaceutical dosage forms such as tablets, pastilles, suppositories,or be packed in capsules.

It is possible and particularly advantageous to produce pharmaceuticalforms with rate-controlled release and improved dissolution rates of theactive ingredients. This was not to be expected in view of the lowsolubility of the active ingredients in aqueous media.

EXAMPLES General Method

Powder mixes of the components were melt kneaded at 145° C. for 5 min.After cooling the solidified melts were ground and sieved. The sievefraction 0.5-1.5 mm was used for the dissolution tests.

The composition of the individual powder mixes is listed in Table 1.

TABLE 1 Example No. 1 2 3 4 5 6 Active ingredient¹⁾ 30 30 30 30 30 40VP-VAC-copolymer²⁾ 65 55 55 60 55 47.1 Surfactant³⁾ 5 15 5 5 4.3 Citricacid 5 HPMC 10 8.6 Surfactant⁴⁾ 15¹⁾4-[[4-[2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]-benzonitrile²⁾Kollidon ® VA64, VP/VAC = 60/40, BASF Aktiengesellschaft³⁾PEG-n-hydrogenated Castoroil ⁴⁾polyoxyethylene polyoxypropyleneblockcopolymer, mean mol. weight 4000 g/mol

The dissolution tests were carried out according to USP XXIII, paddlemodel, pH no change test, 0.1 M HCl, at 37° C., 100 rpm

The results are listed in Table 2.

TABLE 2 Dissolution Rates of particles according to examples 1-6Dissolution [%] Dissolution [%] time Ex. 1 Ex. 2 Ex. 3 Ex. 4 time Ex. 5Ex. 6 [min] (IR) (IR) (IR) (IR) [min] (SR) (SR) 5 53 65 58 57 1 10 73 8688 82 2 15 77 91 95 89 3 20 81 91 96 93 4 30 87 94 99 94 6 60 92 93 9694 8 96 95 120 93 94 97 95 IR: Instant Release SR: Sustained Release

DSC-Measurements were performed with the formulations according toexamples 1 to 6 in open pans (air) at temperatures of from 20→250° C.,with a heating rate of 10° C. per minute. There is no indication ofcrystalline drug substance in the solid dispersions.

1.-15. (canceled)
 16. Rate-controlled release particles, comprising acompound of formula II

an N-oxide, a pharmaceutically acceptable addition salt, a quaternaryamine or a stereochemically isomeric form thereof, wherein-b¹=b²-C(R^(2a))=b³-b⁴=represents a bivalent radical of formula—CH═CH—C(R^(2a))═CH—CH═  (b-1);—N═CH—C(R^(2a))═CH—CH═  (b-2);—CH═N—C(R^(2a))═CH—CH═  (b-3);—N═CH—C(R^(2a))═N—CH═  (b-4);—N═CH—C(R^(2a))═CH—N═  (b-5);—CH═N—C(R^(2a))═N—CH═  (b-6);—N═N—C(R^(2a))═CH—CH═  (b-7); q is 0, 1, 2; or where possible q is 3 or4; R¹ is hydrogen, aryl, formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkyl substituted with formyl,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl; R^(2a) is cyano, aminocarbonyl,mono- or di(methyl)aminocarbonyl, C₁₋₆alkyl substituted with cyano,aminocarbonyl or mono- or di(methyl)aminocarbonyl, C₂₋₆alkenylsubstituted with cyano, or C₂₋₆alkynyl substituted with cyano; each R²independently is hydroxy, halo, C₁₋₆alkyl optionally substituted withcyano or —C(═O)R⁶, C₃₋₇cycloalkyl, C₂₋₆alkenyl optionally substitutedwith one or more halogen atoms or cyano, C₂₋₆alkynyl optionallysubstituted with one or more halogen atoms or cyano, C₁₋₆alkyloxy,C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- ordi(C₁₋₆alkyl)amino, polyhalomethyl, polyhalomethyloxy,polyhalomethylthio, —S(═O)OR⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H,—C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶ or a radical of formula

wherein each A independently is N, CH or CR⁶; B is NH, O, S or NR⁶; p is1 or 2; and R⁶ is methyl, amino, mono- or dimethylamino orpolyhalomethyl; L is C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₃₋₇cycloalkyl, whereby each of said aliphatic group may be substitutedwith one or two substituents independently selected from C₃₋₇cycloalkyl,indolyl or isoindolyl, each optionally substituted with one, two, threeor four substituents each independently selected from halo, C₁₋₆alkyl,hydroxy, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino,polyhalomethyl, polyhalomethyloxy and C₁₋₆alkylcarbonyl, phenyl,pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein each of saidaromatic rings may optionally be substituted with one, two, three, fouror five substituents each independently selected from the substituentsdefined in R²; or L is —X—R³ wherein R³ is phenyl, pyridinyl,pyrimidinyl, pyrazinyl or pyridazinyl, wherein each of said aromaticrings may optionally be substituted with one, two, three, four or fivesubstituents each independently selected from the substituents definedin R²; and X is —NH—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, —S(═O)—or —S(═O)₂—; Q represents hydrogen, C₁₋₆alkyl, halo, polyhaloC₁₋₆alkylor —NR⁴R⁵; and R⁴ and R⁵ are each independently selected from hydrogen,hydroxy, C₁₋₁₂alkyl, C₁₋₁₂alkyloxy, C₁₋₁₂alkylcarbonyl,C₁₋₁₂alkyloxycarbonyl, aryl, amino, mono- or di(C₁₋₁₂alkyl)amino, mono-or di(C₁₋₁₂alkyl)aminocarbonyl wherein each of the aforementionedC₁₋₁₂alkyl groups may optionally and each individually be substitutedwith one or two substituents each independently selected from hydroxy,C₁₋₆alkyloxy, hydroxyc₁₋₆alkyloxy, carboxyl, C₁₋₆alkyloxycarbonyl,cyano, amino, imino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,polyhalomethyloxy, polyhalomethylthio, —S(O)_(p)R⁶, —NH—S(═O)_(p)R⁶,—C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂, —NHC(O)R⁶, —C(═NH)R⁶, aryl and Het; orR⁴ and R⁵ taken together may form pyrrolidinyl, piperidinyl,morpholinyl, azido or mono- or di(C₁₋₁₂alkyl)aminoC₁₋₄-alkylidene; Yrepresents hydroxy, halo, C₃₋₇cycloalkyl, C₂₋₆alkenyl optionallysubstituted with one or more halogen atoms, C₂₋₆alkynyl optionallysubstituted with one or more halogen atoms, C₁₋₆alkyl substituted withcyano or —C(═O)R⁶, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano,nitro, amino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶,—C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁶, —C(NH)R⁶ or aryl; aryl isphenyl or phenyl substituted with one, two, three, four or fivesubstituents each independently selected from halo, C₁₋₆alkyl,C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro, polyhaloC₁₋₆alkyl andpolyhaloC₁₋₆alkyloxy; Het is an aliphatic or aromatic heterocyclicradical; said aliphatic heterocyclic radical is selected frompyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl,tetrahydrofuranyl and tetrahydrothienyl wherein each of said aliphaticheterocyclic radical may optionally be substituted with an oxo group;and said aromatic heterocyclic radical is selected from pyrrolyl,furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinylwherein each of said aromatic heterocyclic radical may optionally besubstituted with hydroxy, as a solid dispersion in a polymeric matrix,wherein the polymeric matrix is consisting of a copolymer ofN-vinylpyrrolidone with vinyl acetate.
 17. Particles according to claim16, wherein the compound of formula (II) is molecularly dispersed in thepolymeric matrix.
 18. Particles according to claim 16, furthercomprising a surfactant.
 19. Particles according to claim 18, whereinthe surfactant is a PEG-n-hydrogenated castor oil.
 20. Particlesaccording to claim 16, wherein the surfactant is a low molecular weightpolyoxyethylene polyoxypropylene block copolymer.
 21. Particlesaccording to claim 16, further comprising citric acid in amounts of upto 5% b.w.
 22. Particles according to claim 16, wherein the copolymer ofN-vinylpyrrolidone is used in amounts of from 40 to 70% b.w. of thetotal weight of the dosage form.
 23. Particles according to claim 22,wherein the copolymer of N-vinylpyrrolidone is used in amounts of from50 to 65% b.w.
 24. Particles according to claim 16, wherein thecontrolled release is an instant release of the drug.
 25. Particlesaccording to claim 16, wherein the controlled release is a sustainedrelease.
 26. Particles according to claim 25, further comprisinghydroxypropyl methyl cellulose in amounts of from 5 to 10% b.w. 27.Particles according to claim 16, obtained by forming a homogeneousmixture of the components in the form of a melt, extruding said mixtureand shaping of the extrudate.
 28. Particles according to claim 16,comprising a compound selected from the group consisting of4-[[4-amino-5-chloro-6-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]-amino]benzonitrile;4-[[5-chloro-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-2-pyrimidin]amino]-benzonitrile;4-[[4-amino-5-chloro-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;4-[[5-bromo-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]-amino]benzonitrile;4-[[4-amino-5-chloro-6-[(4-cyano-2,6-dimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile;4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile;a N-oxide, a pharmaceutically acceptable addition salt or astereochemically isomeric form thereof.
 29. Pharmaceutical dosage form,comprising particles according to claim
 16. 30. Pharmaceutical dosageforms according to claim 29, further comprising one or morepharmaceutically acceptable excipients.
 31. Pharmaceutical dosage formsaccording to claim 29 comprising particles wherein the compound offormula (II) is molecularly dispersed in the polymeric matrix.